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Type 1 diabetes

The importance of early detection to prevent serious complications

Type 1 diabetes (T1D), or autoimmune diabetes, results from the immune destruction of pancreatic insulin-producing beta cells. T1D arises through a complex interaction of genetic, environmental, and epigenetic factors.

T1D is commonly diagnosed in pediatric patients at 2 distinct age ranges, with peaks of diagnosis occurring at ages 4–6 and 10–141—yet 25% to 50% of cases are diagnosed during adulthood.2

Clinical presentation of T1D

Common T1D symptoms in the pediatric population include polyuria, polydipsia, and weight loss3—however, up to 30% of youth present with diabetic ketoacidosis (DKA).4 DKA is a medical emergency, often requiring ICU hospitalization and predisposing patients to additional health complications, such as higher lifetime blood sugar levels, or HbA1c, and adverse impacts to a patient’s memory and IQ. Up to 50% of DKA cases occur in children under 3 years of age with poor socioeconomic backgrounds.5

There is a genetic component to T1D. While up to 90% of individuals who develop T1D have no family history of the disease,6 multiple studies show that a positive family history significantly increases an individual’s risk of developing T1D.1, 7–10

Lifetime risk of T1D development based on family history1,7–10

Family History of T1D Lifetime risk
No family history 0.3%
Mother 1%–4%
Father 6%–9%
Non-twin sibling 10%
Dizygotic twin 8%
Monozygotic twin >50%

Early identification and routine monitoring are crucial for better patient care

The most frequent clinical presentation consists of increased thirst, frequent urination, and weight loss,3 but up to 30% of all children with T1D present with diabetic ketoacidosis (DKA).4 DKA is a medical emergency that requires ICU hospitalization and predisposes to poorer health consequences, including higher lifetime HbA1C and adverse impacts on memory and intelligence quotient. Up to 50% of children under 3 years of age with poor socioeconomic backgrounds present with DKA,5 likely because 90% of T1D patients do not have a family history.6 This means that patients and their families may not recognize the severity of the situation until it is too late and urgent hospitalization is required. The introduction of islet autoantibody (IAb) screening for T1D has resulted in a growing number of IAb+ people monitored for progression toward clinical diabetes. In research studies, such monitoring has been shown to significantly reduce the incidence of DKA at T1D diagnosis.11-16

Epidemiological data show that T1D is diagnosed more frequently in adulthood than in childhood at a median of more than 35 years of age.2,17-18 Despite this, misdiagnoses of T1D in adults remain common and are increasingly likely with age, which increase the likelihood for development of DKA.

Clinical guidelines have been established that provide presymptomatic and symptomatic staging of T1D. Four stages of type 1 diabetes (T1D) are defined by autoantibodies and blood glucose levels (Table 2).19 Autoantibody screening over the past few decades has helped identify individuals at high risk of developing T1D. It has also helped understanding that immune system-mediated destruction of b cells begins long before the onset of symptoms and abnormal blood sugar levels.

Stages of type 1 diabetes19

 

IAbs

Blood sugar

Pathophysiology

5-year risk of clinical diagnosis of T1D

At risk (pre-stage 1 T1D)

Single IAb or transient single IAb

Normoglycemia

Because most PCP are not comfortable managing IAb+ patients, a referral to a specialist or tertiary center is warranted.

Of those testing positive for a single IAb, approximately 14.5% progress to T1D within 10 years, and up to 50% revert to being IAb-.21,22

Stage 1

Pre-symptomatic

≥ 2 IAbs

Normoglycemia

These patients have developed an autoimmune response against multiple autoantibodies, and all of them will eventually progress to clinical disease.21

44%

Stage 2

Pre-symptomatic

≥ 2 IAbs23

Abnormal glucose tolerance defined as IGT (2-hour plasma glucose 140-199 mg/dL) and/or IFG (100-125 mg/dL) and/or HbA1C of 5.7-6.4 or ≥10% increase in HbA1C

CGM values >140 mg/dl for 10% of time over 10 days’ continuous wear, and confirmed by at least one other non-CGM glucose measurement test

Identifies b cell dysfunction and is defined as dysglycemia. Usually detected using standard provocative testing such as the oral glucose tolerance test (OGTT). All these patients should be referred to a diabetologist or endocrinologist to discuss early treatment options in the presence of Stage 2 T1D.20

75%

Stage 3

Symptomatic

≥ 1 autoantibodies

 Clinical diagnosis established andbased on ADA criteria for the diagnosis of diabetes Identifies clinical disease

 

 

ADA, American Diabetes Association; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.23 Some people with confirmed persistent prior multiple autoantibody positivity may revert to single autoantibody status or negative status. In those with multiple antibodies, loss of individual antibodies during follow up is not associated with a slower rate of progression.

How to screen for T1D using antibodies

The American Diabetes Association supports using autoantibody (AAb) screening to diagnose T1D.24 T1D autoantibodies are markers of ongoing damage to insulin-producing beta cells. The four AAbs used in clinical practice to diagnose T1D are: AAbs against insulin (IAA), tyrosine phosphatase IA2 (IA2A), glutamic acid decarboxylase (GAD65), and zinc transporter 8. Numerous clinical trials demonstrate important clinical benefits associated with detecting T1D using an AAb screening approach.25

The recommendation is to use all 4 IAbs (ie, IA2, GAD65, IAA, and ZnT8) for T1D screening, diagnosis, and differential diagnosis from other types of diabetes mellitus. Testing all 4 IAbs at once provides the highest sensitivity for detecting the presence of at least 2 positive autoantibodies,26 which is associated with the eventual development of T1D.27 The American Diabetes Association and European Association for the Study of Diabetes have recently published guidelines for monitoring individuals with islet autoantibody‑positive pre‑stage 3 type 1 diabetes.20 Besides discussing modalities to manage clinically iAb+ patients, these guidelines give particular emphasis to providing these patients with educational and psychological support.

Percentage of patients with autoantibodies detected at T1D onset20

IAB tested

% positive

% positive for at least 2 IABs

IA2A

72

-

GADA

68

-

IAA

55

-

ZnT8A

63

-

IA2A, GADA, IAA

94.2

71.3

IA2A, GADA, IAA, ZnT8A

 98.2

79.4

 

Staging presymptomatic patients using the Diabetes Type 1 Autoantibody Panel

Diabetes Type 1 Autoantibody Panel includes the following components: Glutamic Acid Decarboxylase-65 Antibody (TC 34878), Insulin Autoantibody (TC 36178), IA-2 Antibody (TC 37933), and Zinc Transporter 8 (ZnT8) Antibody (TC 93022). Panel components may be ordered separately.

Comprehensive testing portfolio to identify T1D

With a full suite of AAb tests, we can help you identify more patients with T1D, and identify them earlier, empowering you and your patients to proactively monitor their condition and help reduce the risk of serious complications, including DKA.

Diabetes Type 1 Autoantibody Panel
Glutamic Acid Decarboxylase-65 Antibody
Insulin Autoantibody
IA-2 Antibody
Zinc Transporter 8 (ZnT8) Antibody
 
References
  1. Felner EI, Klitz W, Ham M, et al. Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. Pediatr Diabetes. 2005;6(4):213-220. doi:10.1111/j.1399-543X.2005.00132.x
  2. VanBuecken D, Lord S, Greenbaum CJ. Changing the course of disease in type 1 diabetes. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext. [Internet]. MdText.com, Inc.; 2000. https://www.ncbi.nlm.nih.gov/books/NBK326738/
  3. Roche EF, Menon A, Gill D, et al. Clinical presentation of type 1 diabetes. Pediatr Diabetes. 2005;6(2):75-78. doi:10.1111/j.1399-543x.2005.00110.x
  4. Dabelea D, Rewers A, Stafford JM, et al. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for Diabetes in Youth Study. Pediatrics. 2014;133(4):e938-e945. doi:10.1542/peds.2013-2795
  5. Cherubini V, Grimsmann JM, Åkesson K, et al. Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents. Diabetologia. 2020;63(8):1530-1541. doi:10.1007/s00125-020-05152-1
  6. Sims EK, Besser REJ, Dayan C, et al. Screening for type 1 diabetes in the general population: a status report and perspective. Diabetes. 2022;71(4):610-623. doi:10.2337/dbi20-0054
  7. Group SfDiYS, Liese AD, D’Agostino RB, Jr, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510-1518. doi:10.1542/peds.2006-0690
  8. Lawrence JM, Imperatore G, Dabelea D, et al. Trends in incidence of type 1 diabetes among non-Hispanic white youth in the US, 2002-2009. Diabetes. 2014;63(11):3938-3945. doi:10.2337/db13-1891
  9. Nistico L, Iafusco D, Galderisi A, et al. Emerging effects of early environmental factors over genetic background for type 1 diabetes susceptibility: evidence from a nationwide Italian twin study. J Clin Endocrinol Metab. 2012;97(8):E1483-E1491. doi:10.1210/jc.2011-3457
  10. Patterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027-2033. doi:10.1016/S0140-6736(09)60568-7
  11. Ziegler AG, Kick K, Bonifacio E, et al. Yield of a Public Health Screening of Children for Islet Autoantibodies in Bavaria, Germany. JAMA. 2020;323:339-351. doi:10.1001/jama.2019.21565
  12. Elding Larsson H, Vehik K, Bell R, et al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care. 2011;34:2347-2352. doi:10.2337/dc11-1026
  13. Lundgren M, Sahlin Å, Svensson C, et al. Reduced morbidity at diagnosis and improved glycemic control in children previously enrolled in DiPiS follow-up. Pediatr Diabetes. 2014;15(7):494-501. doi:10.1111/pedi.12151
  14. Wentworth JM, Oakey H, Craig ME, et al. Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand. Pediatr Diabetes. 2022;23:1594-1601. doi:10.1111/pedi.13422
  15. Barker JM, Goehrig SH, Barriga K, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004;27(6):1399-1404. doi:10.2337/diacare.27.6.1399
  16. Jacobsen LM, Vehik K, Veijola R, et al. Heterogeneity of DKA Incidence and Age-Specific Clinical Characteristics in Children Diagnosed With Type 1 Diabetes in the TEDDY Study. Diabetes Care. 2022;45:624-633. doi:10.2337/dc21-0422
  17. Thunander M, Petersson C, Jonzon K, et al. Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res Clin Pract. 2008;82:247-255. doi:10.1016/j.diabres.2008.07.022
  18. Rogers MAM, Kim C, Banerjee T, Lee JM. Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. BMC Med. 2017;15:199. doi:10.1186/s12916-017-0958-6
  19. Couper JJ, Haller MJ, Greenbaum CJ, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2018;19(suppl 27):20-27. doi:10.1111/pedi.12734
  20. Phillip M, Achenbach P, Addala A, et al. Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes. Diabetes Care. 2024. doi:10.2337/dci24-0042
  21. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309:2473-2479. doi:10.1001/jama.2013.6285
  22. Vehik K, Lynch KF, Schatz DA, et al. Reversion of beta-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study. Diabetes Care. 2016;39:1535-1542. doi:10.2337/dc16-0181
  23. Leslie RD, Williams R, Pozzilli P. Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab. 2006;91:1654-1659. doi:10.1210/jc.2005-1623
  24. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S15-S33. doi:10.2337/dc21-S002
  25. Narendran P. Screening for type 1 diabetes: are we nearly there yet? Diabetologia. 2019;62(1):24-27. doi:10.1007/s00125-018-4774-0
  26. Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007;104:17040-17045. doi:10.1073/pnas.0705894104
  27. Greenbaum CJ. A Key to T1D Prevention: Screening and Monitoring Relatives as Part of Clinical Care. Diabetes. 2021;70:1029-1037. doi:10.2337/db20-1112

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